COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients WithBRAFV600–Mutant Melanoma

Abstract

PURPOSE Combination treatment with BRAF and MEK inhibitors has demonstrated benefits on progression-free survival (PFS) and overall survival (OS) and is a standard of care for the treatment of advanced BRAF V600–mutant melanoma. Here, we report the 5-year update from the COLUMBUS trial (ClinicalTrials.gov identifier: NCT01909453 ). METHODS Patients with locally advanced unresectable or metastatic BRAF V600–mutant melanoma, untreated or progressed after first-line immunotherapy, were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, vemurafenib 960 mg twice daily, or encorafenib 300 mg once daily. An updated analysis was conducted 65 months after the last patient was randomly assigned. RESULTS Five hundred seventy-seven patients were randomly assigned: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib. The 5-year PFS and OS rates with encorafenib plus binimetinib were 23% and 35% overall and 31% and 45% in those with normal lactate dehydrogenase levels, respectively. In comparison, the 5-year PFS and OS rates with vemurafenib were 10% and 21% overall and 12% and 28% in those with normal lactate dehydrogenase levels, respectively. The median duration of response with encorafenib plus binimetinib was 18.6 months, with disease control achieved in 92.2% of patients. In comparison, the median duration of response with vemurafenib was 12.3 months, with disease control achieved in 81.2% of patients. Long-term follow-up showed no new safety concerns, and results were consistent with the known tolerability profile of encorafenib plus binimetinib. Interactive visualization of the data presented in this article is available at COLUMBUS dashboard. CONCLUSION In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety profile in patients with BRAF V600–mutant melanoma.

Triple Combination of Immune Checkpoint Inhibitors and BRAF/MEK Inhibitors in BRAFV600 Melanoma: Current Status and Future Perspectives

“…The advent of novel therapeutic options, including both immune checkpoint inhibitors (ICIs) and targeted therapies (TT), has resulted in remarkable advances in the treatment landscape of advanced melanoma [ 1 , 2 , 3 , 4 ]. Presently, in the first-line setting, the median overall survival (OS) of patients treated with combined programmed cell death 1 (PD-1) or cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibition has increased to 72.1 months in phase 3 clinical trials, and data on melanoma-specific survival (MSS) confirm the long-term treatment benefit of this treatment [ 5 ].…”

An effective drug combination for the first-line treatment of advanced gastrointestinal stromal tumor

“…Hence, specific inhibition of the MAPK pathway with MEKinhibitors might not be as helpful in the treatment of GIST as MEK-inhibition is in the treatment of BRAFmutated melanoma. Binimetinib was approved by the Food and Drug Administration (FDA) of the U.S. in 2018 in combination with encorafenib, a BRAF inhibitor, for the treatment of BRAF V600E or V600K mutation-positive advanced melanoma, and combination treatment with a BRAF inhibitor and a MEK inhibitor is now standard of care for treating patients with BRAF V600-mutant advanced melanoma (23). Constitutively active BRAF V600 mutations activate the MAPK signaling pathway driving melanoma cell proliferation, which could be a fundamentally different scenario from GIST KIT mutations that signal also via other pathways.…”

What, if Any, Role Is There for BRAF-Targeted Therapy in BRAF-Mutant Melanoma?

“…In the co-BRIM trial, the 5-year survival of combined vemurafenib/ cobimetinib was 31% and single-agent vemurafenib was 26%. 10 In the article that accompanies this editorial, Dummer et al 11 present the long-term data of the CO-LUMBUS study, which randomly assigned 577 patients with advanced melanoma to encorafenib/binimetinib (192 patients), vemurafenib (191), or encorafenib (194). The 5-year OS of encorafenib/binimetinib was 35%, compared with 21% and 35%, respectively, in the vemurafenib and encorafenib arms.…”

“…Remarkably, the toxicity profile of encorafenib and binimetinib is more favorable than encorafenib alone, thus favoring the use of the approved combination over single-agent encorafenib. 8,11…”

“…In the article that accompanies this editorial, Dummer and colleagues 11 present the long‐term data of the COLUMBUS study. The combination of encorafenib and binimetinib is associated with impressive 5-year progression-free and overall survival in patients with previously untreated, BRAF -mutant advanced melanoma compared with historical controls and consistent with other BRAF/MEK inhibitor combinations.…”